Fluorinated compounds are of high importance in pharmaceuticals and agrochemicals since fluorinated molecules can exhibit advantageous chemical and/or biological profiles when compared with non-fluorinated analogues, for example improved stability, lipophilicity and bioavailability.
As such, there is an increasing need for safe, selective and efficient methods to introduce fluorine atoms into molecules, and a common practice is to produce fluorides from alcohols, and gem-difluorides from carbonyl functional groups, transformations which are commonly referred to as deoxofluorinations reactions.
It is known that SF4 performs deoxofluorinations reactions, but in practice, handling of this highly toxic gas necessitates extensive safety measures. The reactions using SF4 are often undertaken under pressure, require high temperatures (typically 100° C.) and lead to undesired side-products. In an attempt to circumvent these safety issues, various alternative fluorinating agents have been developed. Liquid diethylaminosulfur trifluoride (DAST) was developed (Middleton, W. J. J. Org. Chem. 1975, 40, 574), but it was later determined that this liquid was thermally unstable and highly explosive in nature (Messina, P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137). The manufacture of liquid DAST is also problematic as it requires purification by distillation. This purification step is hazardous, and calls for extensive safety measures and specialized equipment. This is a major cost contributor to this relatively expensive reagent.
In order to develop a safer reagent, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®) was developed (Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999, 71, 7048). It has been reported by differential scanning calorimetry (DSC) that DAST and Deoxofluor® have the same decomposition temperature, but DAST degrades more rapidly with somewhat larger heat evolution.
Whilst Deoxo-Fluor is an adequate substitute for DAST and is indeed less explosive than DAST there are occasions when it remains necessary to use DAST. Thus, and in addition to the aforementioned safety issues there are other significant problems associated with the use of DAST, Deoxo-Fluor and related dialkylaminosulfur trifluoride reagents. Said reagents are fuming liquids difficult to handle in humid environments and react violently with water. Thereby, such reagents do not lend themselves to large scale fluorination processes. The liquids also discolor with aging, and since they have been seen to degrade on storage they sometimes require re-distillation to be satisfactory for use. Furthermore, their explosiveness necessitates strict shipping restrictions and strict legal provisions with respect to their storage and handling.
Salt derivatives of dialkylaminosulfur trifluoride have been known for over three decades. Markovskii et al. were the first to report examples of dialkylaminodifluorosulfinium salts (Markovskii, L. N.; Pashinnik, V. E.; Saenko, E. P. Zh. Org. Khim. 1977, 13, 1116). They describe the reaction of BF3.Et2O with diethylaminosulfurtrifluoride or one of its dimethylamino, piperidino or morpholino analogues to produce the corresponding tetrafluoroborate salt. Later, Cowley et al. (Cowley, A. H.; Pagel, D. J.; Walker, M. L. J. Am. Chem. Soc. 1978, 100, 7065) and Mews and Henle (Mews, R.; Henle, H. J. Fluorine Chem. 1979, 14, 495) reported that other Lewis acid could be used by contacting dimethylaminosulfur trifluoride with BF3, PF5 and AsF5 to form the corresponding dimethylaminodifluorosulfinium salts. The structure of dialkylaminosulfinium salt has been more understood with the further studies of Pauer et al. (Pauer, F.; Erhart, M.; Mews, R.; Stalke, D. Z. Naturforsch., B: Chem. Sci. 1990, 45, 271) in which they have resolved the crystal structure of dimethylaminodifluorosulfinium hexafluoroarsenate. Recently another dialkylaminosulfinium salt has been discovered when Pashinnik et al. (Pashinnik, V. E.; Martynyuk, E. G.; Shermolovich, Y. G. Ukr. Khim. Zh. 2002, 68, 83) reported that morpholinosulfur trifluoride reacts with SeF4 to form morpholinodifluorosulfinium pentafluoroselenate. Although some dialkylaminosulfinium salts have been isolated and characterized, little is known with respect to their chemical reactivity. However, one example of the use of a salt in a deoxofluorination reaction was reported over a decade ago by Pashinnik et al. (Bezuglov, V. V.; Pashinnik, V. E.; Tovstenko, V. I.; Markovskii, L. N.; Freimanis, Y. A.; Serkov, I. V. Russ. J. Bioorg. Chem. 1996, 22, 688) whereby the reaction of an allylic alcohol in a prostaglandin with morpholinodifluorosulfinium tetrafluoroborate in acetonitrile was reported.
Thus, it is clear that there remains a need for safe and effective fluorinating agents which are inexpensive and can be manufactured with relative ease.
The present inventors have published the following reports: Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; LaFlamme, F.; L'Heureux, A. Org. Lett. 2009, 11, 5052; L'Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M J. Org. Chem. 2010, 75, 3401, wherein some details are presented in respect of the present invention.